Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet.

Abstract

BACKGROUND:

NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice.

OBJECTIVE:

To describe a case of NSHPT unresponsive to cinacalcet.

PATIENT AND RESULTS:

A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation.

CONCLUSION:

The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

• Authors: Zeynep Atay, Abdullah Bereket, Belma Haliloglu, Saygin Abali, Tutku Ozdogan, Emel Altuncu, Lucie Canaff, Tatiane Vilaça, Betty Y L Wong, David E C Cole, Geoffrey N Hendy, Serap Turan
• Journal: Bone (Bone) Vol. 64 Pg. 102-7 (Jul 2014) ISSN: 1873-2763 [Electronic] United States
• PMID: 24735972 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Naphthalenes
• Receptors, Calcium-Sensing
• Cinacalcet

Topics

• Cinacalcet
• Female
• Homozygote
• Humans
• Hyperparathyroidism (drug therapy, genetics)
• Infant, Newborn
• Infant, Newborn, Diseases (genetics)
• Male
• Mutation
• Naphthalenes (therapeutic use)
• Pedigree
• Receptors, Calcium-Sensing (genetics)